Muc16 depletion diminishes kras-induced tumorigenesis and metastasis by altering tumor microenvironment factors in pancreatic ductal adenocarcinoma

ABSTRACT MUC16, membrane-bound mucin, plays an oncogenic role in pancreatic ductal adenocarcinoma (PDAC). However, the pathological role of MUC16 in the PDAC progression, tumor

microenvironment, and metastasis in cooperation with KrasG12D and Trp53R172H mutations remains unknown. Deletion of Muc16 with activating mutations KrasG12D/+ and Trp53R172H/+ in mice

significantly decreased progression and prolonged overall survival in KrasG12D/+; Trp53R172H/+; Pdx-1-Cre; Muc16−/− (KPCM) and KrasG12D/+; Pdx-1-Cre; Muc16−/− (KCM), as compared to

KrasG12D/+; Trp53R172H/+; Pdx-1-Cre (KPC) and KrasG12D/+; Pdx-1-Cre (KC) mice, respectively. Muc16 knockout pancreatic tumor (KPCM) displays decreased tumor microenvironment factors and

significantly reduced incidence of liver and lung metastasis compared to KPC. Furthermore, in silico data analysis showed a positive correlation of MUC16 with activated stroma and

metastasis-associated genes. KPCM mouse syngeneic cells had significantly lower metastatic and endothelial cell binding abilities than KPC cells. Similarly, KPCM organoids significantly

decreased the growth rate compared to KPC organoids. Interestingly, RNA-seq data revealed that the cytoskeletal proteins Actg2, Myh11, and Pdlim3 were downregulated in KPCM tumors. Further

knockdown of these genes showed reduced metastatic potential. Overall, our results demonstrate that Muc16 alters the tumor microenvironment factors during pancreatic cancer progression and

metastasis by changing the expression of Actg2, Myh11, and Pdlim3 genes. Access through your institution Buy or subscribe This is a preview of subscription content, access via your

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* Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS LOSS OF THE WILD-TYPE _KRAS_ ALLELE PROMOTES PANCREATIC CANCER

PROGRESSION THROUGH FUNCTIONAL ACTIVATION OF YAP1 Article 18 October 2021 ROFLUMILAST INHIBITS TUMOR GROWTH AND MIGRATION IN STK11/LKB1 DEFICIENT PANCREATIC CANCER Article Open access 09

March 2024 MUC4 LOSS MITIGATES EPIDERMAL GROWTH FACTOR RECEPTOR ACTIVITY ESSENTIAL FOR PDAC TUMORIGENESIS Article 09 January 2023 DATA AVAILABILITY The accession number for RNA sequencing

data of Muc16 knockout pancreatic tumor tissues is GSE212777, and materials associated with the current study are available from the corresponding author upon reasonable request. REFERENCES

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ACKNOWLEDGEMENTS We thank Dr. Richard R. Behringer, Department of Genetics, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA, for

providing the Muc16 whole-body knockout (C57BL/6J) mice. We thank Corinn Grabow for all the technical support. We thank the University of Nebraska Medical Center core facilities such as

Advanced Microscopy Core Facility, Genomics Core Facility, and Tissue Science Facility. This work was, in parts, supported by the support from the National Institutes of Health P01 CA217798,

R01 CA263575, R01 CA256973, R01 CA273349, R01 CA247471, R01 CA254036, R01 CA206444, R01 CA210637, R01 CA228524, F99 CA234962, U01 CA200466, and U01 CA210240, and the Nebraska Department of

Health and Human Services LB595, US Department of Veterans Affairs (I01 BX004676). AUTHOR INFORMATION Author notes * These authors contributed equally: Imayavaramban Lakshmanan,

Saravanakumar Marimuthu. AUTHORS AND AFFILIATIONS * Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA Imayavaramban

Lakshmanan, Saravanakumar Marimuthu, Sanjib Chaudhary, Parthasarathy Seshacharyulu, Satyanarayana Rachagani, Sakthivel Muniyan, Ramakanth Chirravuri-Venkata, Pranita Atri, Sanchita Rauth, 

Rama Krishna Nimmakayala, Jawed Akhtar Siddiqui, Shailendra K. Gautam, Ashu Shah, Gopalakrishnan Natarajan, Seema Parte, Namita Bhyravbhatla, Kavita Mallya, Dhanya Haridas, Sushil Kumar, 

Maneesh Jain, Moorthy P. Ponnusamy & Surinder K. Batra * Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA Geoffrey A. Talmon *

Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE, 68198-4375, USA Lynette M. Smith * Fred & Pamela Buffett Cancer Center,

University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA Apar Kishor Ganti, Maneesh Jain, Moorthy P. Ponnusamy & Surinder K. Batra * Division of Oncology-Hematology, Department

of Internal Medicine, VA Nebraska Western Iowa Health Care System, and University of Nebraska Medical Center, Omaha, NE, 68105-1850, USA Apar Kishor Ganti * Eppley Institute for Research in

Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA Surinder K. Batra Authors * Imayavaramban Lakshmanan View author publications You can also

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author inPubMed Google Scholar * Surinder K. Batra View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS IL, MPP, and SKB conceived and designed

the experiments. IL and SM performed the experiments. IL, SM, PS, and SC assisted with in vivo experiments. Data were collected and analyzed by IL, SM, SC, PS, SR, SM, RCV, PA, SR, RKN, JAS,

SKG, AS, GN, SP, NB, KM, DH, GAT, LMS, SK, AKG, MJ, MPP. The manuscript was written by IL and SM with input from MPP, MJ, and SKB and reviewed by all authors. Statistical analysis and IHC

scoring were done by LMS and GAT, respectively. All authors have read and approved the final manuscript. CORRESPONDING AUTHORS Correspondence to Moorthy P. Ponnusamy or Surinder K. Batra.

ETHICS DECLARATIONS COMPETING INTERESTS SKB is one of the co-founders of Sanguine. Diagnostics and Therapeutics, Inc. The other authors declare no potential conflicts of interest. ADDITIONAL

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Marimuthu, S., Chaudhary, S. _et al._ Muc16 depletion diminishes KRAS-induced tumorigenesis and metastasis by altering tumor microenvironment factors in pancreatic ductal adenocarcinoma.

_Oncogene_ 41, 5147–5159 (2022). https://doi.org/10.1038/s41388-022-02493-6 Download citation * Received: 28 April 2022 * Revised: 23 September 2022 * Accepted: 28 September 2022 *

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