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Here, we explored mechanisms involving the tumor microenvironment (TME) as a potential basis for resistance to targeting KRAS*. Using the inducible KrasG12D;Trp53\u2212\/\u2212 PDAC mouse model, gain-of-function screens of epigenetic regulators identified HDAC5 as the top hit enabling KRAS* independent tumor growth. HDAC5-driven escaper tumors showed a prominent neutrophil-to-macrophage switch relative to KRAS*-driven tumors. Mechanistically, HDAC5 represses Socs3, a negative regulator of chemokine CCL2, resulting in increased CCL2, which recruits CCR2+ macrophages. Correspondingly, enforced Ccl2 promotes macrophage recruitment into the TME and enables tumor recurrence following KRAS* extinction. These tumor-associated macrophages in turn provide cancer cells with trophic support including TGF\u03b2 to enable KRAS* bypass in a SMAD4-dependent manner. Our work uncovers a KRAS* resistance mechanism involving immune cell remodeling of the PDAC TME.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Although KRAS* is required for PDAC tumor maintenance, tumors can recur following KRAS* extinction. The capacity of PDAC cancer cells to alter the TME myeloid cell composition to support KRAS*-independent tumor growth illuminates novel therapeutic targets that may enhance the effectiveness of therapies targeting KRAS* and its pathway components.<\/jats:p>\n                    <jats:p>See related commentary by Carr and Fernandez-Zapico, p. 910.<\/jats:p>\n                    <jats:p>This article is highlighted in the In This Issue feature, p. 890<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-19-0597","type":"journal-article","created":{"date-parts":[[2020,4,27]],"date-time":"2020-04-27T13:59:58Z","timestamp":1587995998000},"page":"1058-1077","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":136,"title":["Tumor Microenvironment Remodeling Enables Bypass of Oncogenic KRAS Dependency in Pancreatic Cancer"],"prefix":"10.1158","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2429-0861","authenticated-orcid":false,"given":"Pingping","family":"Hou","sequence":"first","affiliation":[{"name":"1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas."}]},{"given":"Avnish","family":"Kapoor","sequence":"additional","affiliation":[{"name":"2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas."}]},{"given":"Qiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas."}]},{"given":"Jiexi","family":"Li","sequence":"additional","affiliation":[{"name":"1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas."}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8350-6397","authenticated-orcid":false,"given":"Chang-Jiun","family":"Wu","sequence":"additional","affiliation":[{"name":"2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas."}]},{"given":"Jun","family":"Li","sequence":"additional","affiliation":[{"name":"2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas."}]},{"given":"Zhengdao","family":"Lan","sequence":"additional","affiliation":[{"name":"1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas."}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7739-8913","authenticated-orcid":false,"given":"Ming","family":"Tang","sequence":"additional","affiliation":[{"name":"2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas."}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9263-1883","authenticated-orcid":false,"given":"Xingdi","family":"Ma","sequence":"additional","affiliation":[{"name":"3Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas."}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3796-4447","authenticated-orcid":false,"given":"Jeffrey J.","family":"Ackroyd","sequence":"additional","affiliation":[{"name":"3Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas."}]},{"given":"Raghu","family":"Kalluri","sequence":"additional","affiliation":[{"name":"1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas."}]},{"given":"Jianhua","family":"Zhang","sequence":"additional","affiliation":[{"name":"2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas."}]},{"given":"Shan","family":"Jiang","sequence":"additional","affiliation":[{"name":"4Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas."}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4593-0901","authenticated-orcid":false,"given":"Denise J.","family":"Spring","sequence":"additional","affiliation":[{"name":"1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas."}]},{"given":"Y. 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