Leading Edge
Previews It’s a SMAD/SMAD World Cullen Taniguchi1,* and Anirban Maitra2 1Departments
of Radiation Oncology, Experimental Radiation Oncology, and Cancer Biology of Pathology and Translational Molecular Pathology UT MD Anderson Cancer Center, Houston, TX, 77030, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cell.2015.05.030 2Departments
DPC4/SMAD4 mutations are associated with aggressive pancreatic cancer. In this issue of Cell, Whittle et al. demonstrate that Runx3 expression combined with Dpc4/Smad4 status can predict the metastatic propensity of pancreatic tumors, providing valuable guidance for personalized therapy for patients with pancreatic cancer. The outcomes for pancreatic ductal adenocarcinoma (PDAC) are dismal and have not improved much despite the accumulating knowledge on its biology. One important clinical observation is that, despite the overall poor prognosis, the patterns of treatment failure in PDAC vary significantly. Some patients succumb to overwhelming local tumor burden due to the highly proliferative nature of their cancer cells, while for others, widespread metastases are the major issue. While it is clearly important to tailor the therapeutic options accordingly, we are in need of reliable clinical biomarkers for distinguishing these two groups. Hingorani and colleagues set out to address this issue using a genetically engineered mouse model (GEMM) approach (Whittle et al., 2015). Through careful analysis of Dpc4 haploinsufficient mice, they found that RUNX3 expression, together with the DPC4/SMAD4 level, could potentially help to inform such clinical decisions. The cardinal mutation in PDAC is activated KRAS (>95%) occurring at the earliest stages of the disease, whereas mutations in DPC4/SMAD4 are thought to facilitate the progression of PDAC. Indeed, loss of Smad4 protein correlates with worse clinical outcomes (Biankin et al., 2002), and studies in mouse models have confirmed that loss of Dpc4 confers a metastatic phenotype (Bardeesy et al., 2006). To explore the underlying biology, Whittle et al. generated KPDC mice that harbor an activated Kras allele (KrasLSL-G12D/+), a dominant-negative Trp53 allele (Trp53LSL-R172H/+), and a heterozygous knockout of Dpc4 (Dpc4fl/+), all driven by the pancreas-specific Ptf1a-
Cre, and compared them to the KPC mice with mutations in Kras and Trp53 but wild-type Dpc4. As expected, KPDC mice developed more aggressive tumors, leading to increased mortality compared to the KPC counterparts. Surprisingly, however, KPDC tumors were only aggressive in growth at the primary site but were less metastatic than the KPC controls. It is worth noting that a prior study from this group has shown that, in the absence of concurrent p53 mutations, heterozygous mutation of Dpc4 altered the differentiation state of ductal precursor lesions initiated by oncogenic Kras from pancreatic intraepithelial neoplasia (PanINs) to mucinous cystic neoplasms (MCNs) (Izeradjene et al., 2007). Subsequent progression to invasive PDAC involved loss of heterozygosity of the wild-type Dpc4 allele and mutations in p53 or p16. While these cancers spontaneously developed the same cardinal mutations found in conventional PanIN-to-PDAC, the MCN-toPDAC route led to a lower metastatic burden, consistent with the improved prognosis seen in patients with this route (Wilentz et al., 1999). The authors therefore hypothesized that the chronological order in which key oncogenic mutations occur might affect the ensuing pathology. In the current study, they have demonstrated that, even in the face of concurrent p53 mutation, which now elicits the usual PanIN-PDAC multistep progression, a heterozygous mutation of Dpc4 continues to attenuate the metastatic potential of PDAC. Further investigation revealed that Dpc4 was not the whole story. The authors found that Runx3 expression was elevated by 36-fold in highly meta-
static KPC mice, compared to the locally destructive, albeit oligo-metastatic KPDC mice. Moreover, forced overexpression of Runx3 could override the metastasis-attenuating effect of Dpc4 haploinsufficiency in KPDC cells, enabling the formation of lung metastases in immunocompromised mice. How Runx3 promotes metastasis remains to be fully elucidated. Another intriguing question pertains to the modulation of Runx3 levels by Dpc4/Smad4 gene dosage during cancer development. Although these studies were primarily performed in mice, the findings are potentially valuable for informing clinical decisions. Remember that not all PDAC patients die from metastatic disease. Indeed, many of them suffer great morbidity and mortality from biliary sepsis, gastric outlet obstruction, and acute venous occlusion caused by local tumor growth (Iacobuzio-Donahue, et al., 2009). A predictive measure for the development pattern of PDAC is therefore essential for tailoring treatment. DPC4/ SMAD4 has shown such promise (Crane et al., 2011), and the expression of Smad4 protein is being tested prospectively as a predictive marker of PDAC behavior in the phase II randomized trial RTOG 1201, examining the efficacy of dose-escalated chemoradiation versus conventional chemoradiation or chemotherapy alone. However, currently, Smad4 levels are determined by immunohistochemistry, and the results are categorized as a dichotomous output—either positive or negative. Since this technique cannot distinguish subtle changes of Smad4 expression, including heterozygous DPC4/SMAD4 deletion, it is not
Cell 161, June 4, 2015 ª2015 Elsevier Inc. 1245
REFERENCES Bardeesy, N., Cheng, K.H., Berger, J.H., Chu, G.C., Pahler, J., Olson, P., Hezel, A.F., Horner, J., Lauwers, G.Y., Hanahan, D., and DePinho, R.A. (2006). Genes Dev. 20, 3130–3146. Biankin, A.V., Morey, A.L., Lee, C.S., Kench, J.G., Biankin, S.A., Hook, H.C., Head, D.R., Hugh, T.B., Sutherland, R.L., and Henshall, S.M. (2002). J. Clin. Oncol. 20, 4531–4542. Crane, C.H., Varadhachary, G.R., Yordy, J.S., Staerkel, G.A., Javle, M.M., Safran, H., Haque, W., Hobbs, B.D., Krishnan, S., Fleming, J.B., et al. (2011). J. Clin. Oncol. 29, 3037–3043.
Figure 1. Runx3 Could Improve the Utility of Smad4 as a Biomarker of Pancreatic Cancer Biology Patients with the combination of detectable Smad4 expression and a low level of Runx3 may benefit from aggressive local therapy because of the proliferative nature of the tumors. In contrast, tumors with undetectable Smad4 or a high level of Runx3 tend to be highly metastatic, and the therapeutic regime should be tailored accordingly.
surprising that positive Smad4 expression alone has not been widely used for predictive purposes (Winter et al., 2013). The study from Whittle et al. proposed a potential solution of using Runx3 expression in tumor cells for predicting the behavior of Smad4-positive tumors (Figure 1). For clinical applications, this idea needs to be further tested in multiple retrospective data sets. It is also important to understand whether the predictive power would also apply to common com-
binations of PDAC mutations that were not explicitly examined in this study, such as those involving CDKN2A. Nonetheless, identifying RUNX3 as a metastatic switch in this context is encouraging, and with this knowledge, oncologists could personalize therapeutic approaches by treating locally aggressive tumors with higher radiation doses and/ or more liberal criteria for surgery but prioritizing chemotherapy for those with a metastatic potential.
Iacobuzio-Donahue, C.A., Fu, B., Yachida, S., Luo, M., Abe, H., Henderson, C.M., Vilardell, F., Wang, Z., Keller, J.W., Banerjee, P., et al. (2009). J. Clin. Oncol. 27, 1806–1813. Izeradjene, K., Combs, C., Best, M., Gopinathan, A., Wagner, A., Grady, W.M., Deng, C.X., Hruban, R.H., Adsay, N.V., Tuveson, D.A., and Hingorani, S.R. (2007). Cancer Cell 11, 229–243. Whittle, M.C., Izeradjene, K., Rani, P.G., Feng, L., Carlson, M.A., Delgiornio, K.E., Wood, L.D., Goggins, M., Hruban, R.H., Chang, A.E., et al. (2015). Cell 161, this issue, 1345–1360. Wilentz, R.E., Albores-Saavedra, J., Zahurak, M., Talamini, M.A., Yeo, C.J., Cameron, J.L., and Hruban, R.H. (1999). Am. J. Surg. Pathol. 23, 1320– 1327. Winter, J.M., Tang, L.H., Klimstra, D.S., Liu, W., Linkov, I., Brennan, M.F., D’Angelica, M.I., DeMatteo, R.P., Fong, Y., Jarnagin, W.R., et al. (2013). Ann. Surg. 258, 331–335.
Dying mRNA Tells a Story of Its Life Edward W.J. Wallace1,* and D. Allan Drummond1,* 1Department of Biochemistry & Molecular Biology, The University of Chicago, Chicago, IL 60637, USA *Correspondence: [email protected] (E.W.J.W.), [email protected] (D.A.D.) http://dx.doi.org/10.1016/j.cell.2015.05.043
In this issue of Cell, Pelechano et al. report that sequencing of mRNA decay intermediates shows surprisingly tight coupling of a major decay pathway to the movement of the last translating ribosome, revealing stress- and starvation-dependent modulation of translation elongation. Messenger RNA lives an eventful life— each molecule is transcribed from DNA and then may be spliced, polyadenylated, modified, exported, transported, and
translated before succumbing to degradation. Stages in the mRNA life cycle often overlap in important ways: splicing acts as a co-transcriptional quality con-
1246 Cell 161, June 4, 2015 ª2015 Elsevier Inc.
trol checkpoint (Chathoth et al., 2014), mRNA-ribosome complexes are cotranslationally localized to membranes by the signal recognition particle, and mRNA is
Previews It’s a SMAD/SMAD World Cullen Taniguchi1,* and Anirban Maitra2 1Departments
of Radiation Oncology, Experimental Radiation Oncology, and Cancer Biology of Pathology and Translational Molecular Pathology UT MD Anderson Cancer Center, Houston, TX, 77030, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cell.2015.05.030 2Departments
DPC4/SMAD4 mutations are associated with aggressive pancreatic cancer. In this issue of Cell, Whittle et al. demonstrate that Runx3 expression combined with Dpc4/Smad4 status can predict the metastatic propensity of pancreatic tumors, providing valuable guidance for personalized therapy for patients with pancreatic cancer. The outcomes for pancreatic ductal adenocarcinoma (PDAC) are dismal and have not improved much despite the accumulating knowledge on its biology. One important clinical observation is that, despite the overall poor prognosis, the patterns of treatment failure in PDAC vary significantly. Some patients succumb to overwhelming local tumor burden due to the highly proliferative nature of their cancer cells, while for others, widespread metastases are the major issue. While it is clearly important to tailor the therapeutic options accordingly, we are in need of reliable clinical biomarkers for distinguishing these two groups. Hingorani and colleagues set out to address this issue using a genetically engineered mouse model (GEMM) approach (Whittle et al., 2015). Through careful analysis of Dpc4 haploinsufficient mice, they found that RUNX3 expression, together with the DPC4/SMAD4 level, could potentially help to inform such clinical decisions. The cardinal mutation in PDAC is activated KRAS (>95%) occurring at the earliest stages of the disease, whereas mutations in DPC4/SMAD4 are thought to facilitate the progression of PDAC. Indeed, loss of Smad4 protein correlates with worse clinical outcomes (Biankin et al., 2002), and studies in mouse models have confirmed that loss of Dpc4 confers a metastatic phenotype (Bardeesy et al., 2006). To explore the underlying biology, Whittle et al. generated KPDC mice that harbor an activated Kras allele (KrasLSL-G12D/+), a dominant-negative Trp53 allele (Trp53LSL-R172H/+), and a heterozygous knockout of Dpc4 (Dpc4fl/+), all driven by the pancreas-specific Ptf1a-
Cre, and compared them to the KPC mice with mutations in Kras and Trp53 but wild-type Dpc4. As expected, KPDC mice developed more aggressive tumors, leading to increased mortality compared to the KPC counterparts. Surprisingly, however, KPDC tumors were only aggressive in growth at the primary site but were less metastatic than the KPC controls. It is worth noting that a prior study from this group has shown that, in the absence of concurrent p53 mutations, heterozygous mutation of Dpc4 altered the differentiation state of ductal precursor lesions initiated by oncogenic Kras from pancreatic intraepithelial neoplasia (PanINs) to mucinous cystic neoplasms (MCNs) (Izeradjene et al., 2007). Subsequent progression to invasive PDAC involved loss of heterozygosity of the wild-type Dpc4 allele and mutations in p53 or p16. While these cancers spontaneously developed the same cardinal mutations found in conventional PanIN-to-PDAC, the MCN-toPDAC route led to a lower metastatic burden, consistent with the improved prognosis seen in patients with this route (Wilentz et al., 1999). The authors therefore hypothesized that the chronological order in which key oncogenic mutations occur might affect the ensuing pathology. In the current study, they have demonstrated that, even in the face of concurrent p53 mutation, which now elicits the usual PanIN-PDAC multistep progression, a heterozygous mutation of Dpc4 continues to attenuate the metastatic potential of PDAC. Further investigation revealed that Dpc4 was not the whole story. The authors found that Runx3 expression was elevated by 36-fold in highly meta-
static KPC mice, compared to the locally destructive, albeit oligo-metastatic KPDC mice. Moreover, forced overexpression of Runx3 could override the metastasis-attenuating effect of Dpc4 haploinsufficiency in KPDC cells, enabling the formation of lung metastases in immunocompromised mice. How Runx3 promotes metastasis remains to be fully elucidated. Another intriguing question pertains to the modulation of Runx3 levels by Dpc4/Smad4 gene dosage during cancer development. Although these studies were primarily performed in mice, the findings are potentially valuable for informing clinical decisions. Remember that not all PDAC patients die from metastatic disease. Indeed, many of them suffer great morbidity and mortality from biliary sepsis, gastric outlet obstruction, and acute venous occlusion caused by local tumor growth (Iacobuzio-Donahue, et al., 2009). A predictive measure for the development pattern of PDAC is therefore essential for tailoring treatment. DPC4/ SMAD4 has shown such promise (Crane et al., 2011), and the expression of Smad4 protein is being tested prospectively as a predictive marker of PDAC behavior in the phase II randomized trial RTOG 1201, examining the efficacy of dose-escalated chemoradiation versus conventional chemoradiation or chemotherapy alone. However, currently, Smad4 levels are determined by immunohistochemistry, and the results are categorized as a dichotomous output—either positive or negative. Since this technique cannot distinguish subtle changes of Smad4 expression, including heterozygous DPC4/SMAD4 deletion, it is not
Cell 161, June 4, 2015 ª2015 Elsevier Inc. 1245
REFERENCES Bardeesy, N., Cheng, K.H., Berger, J.H., Chu, G.C., Pahler, J., Olson, P., Hezel, A.F., Horner, J., Lauwers, G.Y., Hanahan, D., and DePinho, R.A. (2006). Genes Dev. 20, 3130–3146. Biankin, A.V., Morey, A.L., Lee, C.S., Kench, J.G., Biankin, S.A., Hook, H.C., Head, D.R., Hugh, T.B., Sutherland, R.L., and Henshall, S.M. (2002). J. Clin. Oncol. 20, 4531–4542. Crane, C.H., Varadhachary, G.R., Yordy, J.S., Staerkel, G.A., Javle, M.M., Safran, H., Haque, W., Hobbs, B.D., Krishnan, S., Fleming, J.B., et al. (2011). J. Clin. Oncol. 29, 3037–3043.
Figure 1. Runx3 Could Improve the Utility of Smad4 as a Biomarker of Pancreatic Cancer Biology Patients with the combination of detectable Smad4 expression and a low level of Runx3 may benefit from aggressive local therapy because of the proliferative nature of the tumors. In contrast, tumors with undetectable Smad4 or a high level of Runx3 tend to be highly metastatic, and the therapeutic regime should be tailored accordingly.
surprising that positive Smad4 expression alone has not been widely used for predictive purposes (Winter et al., 2013). The study from Whittle et al. proposed a potential solution of using Runx3 expression in tumor cells for predicting the behavior of Smad4-positive tumors (Figure 1). For clinical applications, this idea needs to be further tested in multiple retrospective data sets. It is also important to understand whether the predictive power would also apply to common com-
binations of PDAC mutations that were not explicitly examined in this study, such as those involving CDKN2A. Nonetheless, identifying RUNX3 as a metastatic switch in this context is encouraging, and with this knowledge, oncologists could personalize therapeutic approaches by treating locally aggressive tumors with higher radiation doses and/ or more liberal criteria for surgery but prioritizing chemotherapy for those with a metastatic potential.
Iacobuzio-Donahue, C.A., Fu, B., Yachida, S., Luo, M., Abe, H., Henderson, C.M., Vilardell, F., Wang, Z., Keller, J.W., Banerjee, P., et al. (2009). J. Clin. Oncol. 27, 1806–1813. Izeradjene, K., Combs, C., Best, M., Gopinathan, A., Wagner, A., Grady, W.M., Deng, C.X., Hruban, R.H., Adsay, N.V., Tuveson, D.A., and Hingorani, S.R. (2007). Cancer Cell 11, 229–243. Whittle, M.C., Izeradjene, K., Rani, P.G., Feng, L., Carlson, M.A., Delgiornio, K.E., Wood, L.D., Goggins, M., Hruban, R.H., Chang, A.E., et al. (2015). Cell 161, this issue, 1345–1360. Wilentz, R.E., Albores-Saavedra, J., Zahurak, M., Talamini, M.A., Yeo, C.J., Cameron, J.L., and Hruban, R.H. (1999). Am. J. Surg. Pathol. 23, 1320– 1327. Winter, J.M., Tang, L.H., Klimstra, D.S., Liu, W., Linkov, I., Brennan, M.F., D’Angelica, M.I., DeMatteo, R.P., Fong, Y., Jarnagin, W.R., et al. (2013). Ann. Surg. 258, 331–335.
Dying mRNA Tells a Story of Its Life Edward W.J. Wallace1,* and D. Allan Drummond1,* 1Department of Biochemistry & Molecular Biology, The University of Chicago, Chicago, IL 60637, USA *Correspondence: [email protected] (E.W.J.W.), [email protected] (D.A.D.) http://dx.doi.org/10.1016/j.cell.2015.05.043
In this issue of Cell, Pelechano et al. report that sequencing of mRNA decay intermediates shows surprisingly tight coupling of a major decay pathway to the movement of the last translating ribosome, revealing stress- and starvation-dependent modulation of translation elongation. Messenger RNA lives an eventful life— each molecule is transcribed from DNA and then may be spliced, polyadenylated, modified, exported, transported, and
translated before succumbing to degradation. Stages in the mRNA life cycle often overlap in important ways: splicing acts as a co-transcriptional quality con-
1246 Cell 161, June 4, 2015 ª2015 Elsevier Inc.
trol checkpoint (Chathoth et al., 2014), mRNA-ribosome complexes are cotranslationally localized to membranes by the signal recognition particle, and mRNA is
