Understanding adenoma progression: Interplay among tissue microenvironment, clonal architecture, and gut microbiome

总结 结直肠癌（CRC）在美国每年影响约145，000人，是第三大常见癌症原因 相关死亡。CRC起源于癌前病变的早期病变;这些早期病变是结肠腺瘤 和锯齿状无蒂病变（SSL）。结肠腺瘤占CRC癌前病变的80-85%， 通过早期腺瘤→晚期腺瘤→ CRC序列进展为CRC。鉴于其良好的特性， 由于腺瘤的临床自然史，我们计划将其作为早期病变进行研究，并确定其机制 参与早期癌前病变的形成和发展。值得注意的是，只有少数早期腺瘤 进展为晚期腺瘤（AA），甚至更少进展为CRC。我们的团队和其他人已经证明 在大多数情况下，单独的突变不足以引起腺瘤的发生和/或进展。 可能有多种腺瘤非自主机制与肿瘤细胞中的DNA改变协同作用。 腺瘤引起进展，这些机制可能在受影响的离散亚群中起作用。 个体我们和其他人已经观察到改变，如组织衰老，高癌症驱动基因， 人类正常结肠中的突变负荷、异常DNA甲基化模式和肠道微生物群失调 晚期腺瘤和结直肠癌患者。我们称具有这些特征的正常结肠为“启动结肠” 并提出这些特征是影响腺瘤发生和发展的合理机制。 基于这些观察和我们先前的研究，我们假设早期病变进展需要一套 这些行为是由腺瘤自主因素（例如癌症驱动因素）诱导的 基因突变）和腺瘤非自主性因素从“启动结肠”或腺瘤微环境。 我们提出的研究将整合基础和转化癌症研究项目，以迭代地检查 腺瘤、结肠“启动”微环境和宿主之间的直接因果关系和相互作用， 系统性因素作为腺瘤启动和/或进展的“共同组织者”。具体目标是： 目的1）确定鉴别非进展期腺瘤的细胞自主性分子因子 和调节非晚期腺瘤进展。（项目1和2） 目的2）从“致敏”结肠和腺瘤中确定腺瘤非自主性因子 与晚期人类结肠腺瘤相关的微环境和调节腺瘤进展。 这些因素将包括以下“启动”结肠状态：1.衰老状态; 2.癌症驱动基因突变 负担; 3.肠道微生物组状态; 4.结肠甲基化组，和5.结肠免疫活性状态。（项目1-3） 目的3）探讨腺瘤的自主性和非自主性因素在腺瘤中的作用 微环境和“启动的”结肠协同驱动腺瘤形成和进展。（项目1-3）

SUMMARY Colorectal cancer (CRC) affects ~145,000 people/year in the US and is the 3rd most common cause of cancer related deaths. CRC arises from early lesions that are pre-cancerous; these early lesions are colon adenomas and serrated sessile lesions (SSL). Colon adenomas account for 80-85% of the CRC precancerous lesions and progress to CRC via an early adenomaàadvanced adenomaàCRC sequence. In light of the well characterized clinical natural history of adenomas, we plan to study them as early lesions and to determine the mechanisms involved in the formation and progression of early precancerous lesions. Notably, only a few early adenomas will progress to advanced adenomas (AA) and even fewer will progress to CRC. Our group and others have shown that mutations alone are not sufficient to cause adenoma initiation and/or progression in the majority of cases. There are likely multiple adenoma nonautonomous mechanisms that cooperate with the DNA alterations in the adenomas to cause progression, and these mechanisms are likely operative in discrete subsets of affected individuals. We and others have observed alterations, such as tissue senescence, high cancer driver gene mutation loads, aberrant DNA methylation patterns, and dysbiotic gut microbiomes, in the normal colon of people with advanced adenomas and CRC patients. We have termed normal colons with these features “primed colons” and propose that these features are plausible mechanisms that affect adenoma initiation and progression. Based on these observations and our prior studies, we hypothesize that early lesion progression requires a suite of hallmark behaviors and that these behaviors are induced by adenoma autonomous factors (e.g. cancer driver gene mutations) and adenoma nonautonomous factors from the “primed colon” or adenoma microenvironment. Our proposed studies will integrate basic and translational cancer research Projects to iteratively examine the direct causal relationships and interactions of adenomas, the colon “primed” microenvironment, and host- systemic factors as “co-organizers” of adenoma initiation and/or progression. The Specific Aims are: Aim 1) To determine the adenoma cell autonomous molecular factors that distinguish nonadvanced adenomas from advanced adenomas and that regulate nonadvanced adenoma progression. (Projects 1 and 2) Aim 2) To determine the adenoma nonautonomous factors from the “primed” colon and from the adenoma microenvironment that associate with advanced human colon adenomas and regulate adenoma progression. These factors will include the following “primed” colon states: 1. senescence state; 2. cancer driver gene mutation burden; 3. gut microbiome state; 4. colon methylome, and 5. colon immune activity state. (Projects 1-3) Aim 3)To determine how adenoma autonomous and nonautonomous factors from the adenoma microenvironment and the “primed” colon cooperate to drive adenoma formation and progression.(Projcts 1-3)