Data from Gain-of-Function p53 Mutation Acts as a Genetic Switch for TGFβ Signaling–Induced Epithelial-to-Mesenchymal Transition in Intestinal Tumors

Abstract

<div>Abstract<p>Signaling by TGFβ family cytokines plays a tumor-suppressive role by inducing cell differentiation, while it promotes malignant progression through epithelial-to-mesenchymal transition (EMT). Identification of the mechanisms regulating the switch from tumor suppression to tumor promotion could identify strategies for cancer prevention and treatment. To identify the key genetic alterations that determine the outcome of TGFβ signaling, we used mouse intestinal tumor-derived organoids carrying multiple driver mutations in various combinations to examine the relationship between genotypes and responses to the TGFβ family cytokine activin A. <i>Kras<sup>G12D</sup></i> mutation protected organoid cells from activin A–induced growth suppression by inhibiting p21 and p27 expression. Furthermore, <i>Trp53<sup>R270H</sup></i> gain-of-function (GOF) mutation together with loss of wild-type <i>Trp53</i> by loss of heterozygosity (LOH) promoted activin A–induced partial EMT with formation of multiple protrusions on the organoid surface, which was associated with increased metastatic incidence. Histologic analysis confirmed that tumor cells at the protrusions showed loss of apical–basal polarity and glandular structure. RNA sequencing analysis indicated that expression of <i>Hmga2</i>, encoding a cofactor of the SMAD complex that induces EMT transcription factors, was significantly upregulated in organoids with <i>Trp53</i> GOF/LOH alterations. Importantly, loss of HMGA2 suppressed expression of <i>Twist1</i> and blocked activin A–induced partial EMT and metastasis in <i>Trp53</i> GOF/LOH organoids. These results indicate that <i>TP53</i> GOF/LOH is a key genetic state that primes for TGFβ family-induced partial EMT and malignant progression of colorectal cancer. Activin signaling may be an effective therapeutic target for colorectal cancer harboring <i>TP53</i> GOF mutations.</p>Significance:<p><i>KRAS</i> and <i>TP53</i> mutations shift activin-mediated signaling to overcome growth inhibition and promote partial EMT, identifying a subset of patients with colorectal cancer that could benefit from inhibition of TGFβ signaling.</p></div>