MYC Levels Regulate Metastatic Heterogeneity in Pancreatic Adenocarcinoma

Ravikanth Maddipati; Robert J. Norgard; Timour Baslan; Komal S. Rathi; Amy Zhang; Asal Saeid; Taku Higashihara; Feng Wu; Angad Kumar; Valli Annamalai; Saurav Bhattacharya; Pichai Raman; Christian A. Adkisson; Jason R. Pitarresi; Maximilian D. Wengyn; Taiji Yamazoe; Jinyang Li; David Balli; Michael J. Lariviere; Tuong Vi C. Ngo; Ian W. Folkert; Ian D. Millstein; Jonathan Bermeo; Erica L. Carpenter; John C. McAuliffe; Maja H. Oktay; Rolf A. Brekken; Scott W. Lowe; Christine A. Iacobuzio-Donahue; Faiyaz Notta; Ben Z. Stanger

doi:10.1158/2159-8290.CD-20-1826

MYC Levels Regulate Metastatic Heterogeneity in Pancreatic Adenocarcinoma

Ravikanth Maddipati, Robert J. Norgard, Timour Baslan, Komal S. Rathi, Amy Zhang, Asal Saeid, Taku Higashihara, Feng Wu, Angad Kumar, Valli Annamalai, Saurav Bhattacharya, Pichai Raman, Christian A. Adkisson, Jason R. Pitarresi, Maximilian D. Wengyn, Taiji Yamazoe, Jinyang Li, David Balli, Michael J. Lariviere, Tuong Vi C. NgoIan W. Folkert, Ian D. Millstein, Jonathan Bermeo, Erica L. Carpenter, John C. McAuliffe, Maja H. Oktay, Rolf A. Brekken, Scott W. Lowe, Christine A. Iacobuzio-Donahue, Faiyaz Notta, Ben Z. Stanger

Research output: Contribution to journal › Article › peer-review

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Abstract

The degree of metastatic disease varies widely among patients with cancer and affects clinical outcomes. However, the biological and functional differences that drive the extent of metastasis are poorly understood. We analyzed primary tumors and paired metastases using a multifluorescent lineage-labeled mouse model of pancreatic ductal adenocarcinoma (PDAC)—a tumor type in which most patients present with metastases. Genomic and transcriptomic analysis revealed an association between metastatic burden and gene amplification or transcriptional upregulation of MYC and its downstream targets. Functional experiments showed that MYC promotes metastasis by recruiting tumor-associated macrophages, leading to greater bloodstream intravasation. Consistent with these findings, metastatic progression in human PDAC was associated with activation of MYC signaling pathways and enrichment for MYC amplifications specifically in metastatic patients. Collectively, these results implicate MYC activity as a major determinant of metastatic burden in advanced PDAC. SIGNIFICANCE: Here, we investigate metastatic variation seen clinically in patients with PDAC and murine PDAC tumors and identify MYC as a major driver of this heterogeneity.

Original language	English (US)
Pages (from-to)	542-561
Number of pages	20
Journal	Cancer discovery
Volume	12
Issue number	2
DOIs	https://doi.org/10.1158/2159-8290.CD-20-1826
State	Published - Feb 1 2022

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Oncology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/2159-8290.CD-20-1826

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Maddipati, R., Norgard, R. J., Baslan, T., Rathi, K. S., Zhang, A., Saeid, A., Higashihara, T., Wu, F., Kumar, A., Annamalai, V., Bhattacharya, S., Raman, P., Adkisson, C. A., Pitarresi, J. R., Wengyn, M. D., Yamazoe, T., Li, J., Balli, D., Lariviere, M. J., ... Stanger, B. Z. (2022). MYC Levels Regulate Metastatic Heterogeneity in Pancreatic Adenocarcinoma. Cancer discovery, 12(2), 542-561. https://doi.org/10.1158/2159-8290.CD-20-1826

Maddipati, R, Norgard, RJ, Baslan, T, Rathi, KS, Zhang, A, Saeid, A, Higashihara, T, Wu, F, Kumar, A, Annamalai, V, Bhattacharya, S, Raman, P, Adkisson, CA, Pitarresi, JR, Wengyn, MD, Yamazoe, T, Li, J, Balli, D, Lariviere, MJ, Ngo, TVC, Folkert, IW, Millstein, ID, Bermeo, J, Carpenter, EL, McAuliffe, JC , Oktay, MH, Brekken, RA, Lowe, SW, Iacobuzio-Donahue, CA, Notta, F & Stanger, BZ 2022, 'MYC Levels Regulate Metastatic Heterogeneity in Pancreatic Adenocarcinoma', Cancer discovery, vol. 12, no. 2, pp. 542-561. https://doi.org/10.1158/2159-8290.CD-20-1826

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title = "MYC Levels Regulate Metastatic Heterogeneity in Pancreatic Adenocarcinoma",

abstract = "The degree of metastatic disease varies widely among patients with cancer and affects clinical outcomes. However, the biological and functional differences that drive the extent of metastasis are poorly understood. We analyzed primary tumors and paired metastases using a multifluorescent lineage-labeled mouse model of pancreatic ductal adenocarcinoma (PDAC)—a tumor type in which most patients present with metastases. Genomic and transcriptomic analysis revealed an association between metastatic burden and gene amplification or transcriptional upregulation of MYC and its downstream targets. Functional experiments showed that MYC promotes metastasis by recruiting tumor-associated macrophages, leading to greater bloodstream intravasation. Consistent with these findings, metastatic progression in human PDAC was associated with activation of MYC signaling pathways and enrichment for MYC amplifications specifically in metastatic patients. Collectively, these results implicate MYC activity as a major determinant of metastatic burden in advanced PDAC. SIGNIFICANCE: Here, we investigate metastatic variation seen clinically in patients with PDAC and murine PDAC tumors and identify MYC as a major driver of this heterogeneity.",

author = "Ravikanth Maddipati and Norgard, {Robert J.} and Timour Baslan and Rathi, {Komal S.} and Amy Zhang and Asal Saeid and Taku Higashihara and Feng Wu and Angad Kumar and Valli Annamalai and Saurav Bhattacharya and Pichai Raman and Adkisson, {Christian A.} and Pitarresi, {Jason R.} and Wengyn, {Maximilian D.} and Taiji Yamazoe and Jinyang Li and David Balli and Lariviere, {Michael J.} and Ngo, {Tuong Vi C.} and Folkert, {Ian W.} and Millstein, {Ian D.} and Jonathan Bermeo and Carpenter, {Erica L.} and McAuliffe, {John C.} and Oktay, {Maja H.} and Brekken, {Rolf A.} and Lowe, {Scott W.} and Iacobuzio-Donahue, {Christine A.} and Faiyaz Notta and Stanger, {Ben Z.}",

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doi = "10.1158/2159-8290.CD-20-1826",

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AU - Maddipati, Ravikanth

AU - Norgard, Robert J.

AU - Baslan, Timour

AU - Rathi, Komal S.

AU - Zhang, Amy

AU - Saeid, Asal

AU - Higashihara, Taku

AU - Wu, Feng

AU - Kumar, Angad

AU - Annamalai, Valli

AU - Bhattacharya, Saurav

AU - Raman, Pichai

AU - Adkisson, Christian A.

AU - Pitarresi, Jason R.

AU - Wengyn, Maximilian D.

AU - Yamazoe, Taiji

AU - Li, Jinyang

AU - Balli, David

AU - Lariviere, Michael J.

AU - Ngo, Tuong Vi C.

AU - Folkert, Ian W.

AU - Millstein, Ian D.

AU - Bermeo, Jonathan

AU - Carpenter, Erica L.

AU - McAuliffe, John C.

AU - Oktay, Maja H.

AU - Brekken, Rolf A.

AU - Lowe, Scott W.

AU - Iacobuzio-Donahue, Christine A.

AU - Notta, Faiyaz

AU - Stanger, Ben Z.

PY - 2022/2/1

Y1 - 2022/2/1

N2 - The degree of metastatic disease varies widely among patients with cancer and affects clinical outcomes. However, the biological and functional differences that drive the extent of metastasis are poorly understood. We analyzed primary tumors and paired metastases using a multifluorescent lineage-labeled mouse model of pancreatic ductal adenocarcinoma (PDAC)—a tumor type in which most patients present with metastases. Genomic and transcriptomic analysis revealed an association between metastatic burden and gene amplification or transcriptional upregulation of MYC and its downstream targets. Functional experiments showed that MYC promotes metastasis by recruiting tumor-associated macrophages, leading to greater bloodstream intravasation. Consistent with these findings, metastatic progression in human PDAC was associated with activation of MYC signaling pathways and enrichment for MYC amplifications specifically in metastatic patients. Collectively, these results implicate MYC activity as a major determinant of metastatic burden in advanced PDAC. SIGNIFICANCE: Here, we investigate metastatic variation seen clinically in patients with PDAC and murine PDAC tumors and identify MYC as a major driver of this heterogeneity.

AB - The degree of metastatic disease varies widely among patients with cancer and affects clinical outcomes. However, the biological and functional differences that drive the extent of metastasis are poorly understood. We analyzed primary tumors and paired metastases using a multifluorescent lineage-labeled mouse model of pancreatic ductal adenocarcinoma (PDAC)—a tumor type in which most patients present with metastases. Genomic and transcriptomic analysis revealed an association between metastatic burden and gene amplification or transcriptional upregulation of MYC and its downstream targets. Functional experiments showed that MYC promotes metastasis by recruiting tumor-associated macrophages, leading to greater bloodstream intravasation. Consistent with these findings, metastatic progression in human PDAC was associated with activation of MYC signaling pathways and enrichment for MYC amplifications specifically in metastatic patients. Collectively, these results implicate MYC activity as a major determinant of metastatic burden in advanced PDAC. SIGNIFICANCE: Here, we investigate metastatic variation seen clinically in patients with PDAC and murine PDAC tumors and identify MYC as a major driver of this heterogeneity.

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MYC Levels Regulate Metastatic Heterogeneity in Pancreatic Adenocarcinoma

Abstract

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