Humam Kadara, Professor in Lung Cancer at MD Anderson Cancer Center, shared a post on LinkedIn about a paper he co-authored with colleagues published in Cancer Cell by Cell Press:
“Very excited to have our work on spatial profiling of lung precursor lesions and invasive lung cancers out in Cancer Cell by Cell Press. Here is a run down of our major findings!
We studied cohorts of normal lung tissues, precursor/preinvasive lesions and invasive lung cancer by multiple single-cell and spatial profiling modalities. We first find that invasive lung cancers, naturally, have more complex spatial expression patterns than their premalignant counterparts.
Phylogenetic reconstruction using our spatial transcriptomics analysis found that the earliest clones mapped to reactive pneumocytes, the histological resemblant of KRT8+ alveolar cells (KACs)/intermediates! This was super exciting! We previously reported that these transitional cells were not so transitional, they were stuck in limbo and acted as progenitors of lung adenocarcinoma.
Remarkably, KACs had uniquely high expression of ‘drivers’ of inflammation (IL1R1) and were present in niches that were rich with IL1B high myeloid (macrophages) cells. This epithelial-proinflammatory niche was disease stage-specific. Unlike oncogenic properties which we believe accumulate over the lifetime of the lesion, these niches peaked in early precursor lesions and faded in more advanced stages.
We functionally validated these KAC/epithelial-proinflammatory niches in lung carcinogenesis models showing that IL-1B treatment or co-culture with interstitial macrophages act as mitogens for KRT8+ high alveolar cells. We found that targeting IL-1B by neutralizing antibodies, including when combined with PD-1 blockade, was effective in preventing formation of precancerous lesions and their progression to adenocarcinomas. These effects were associated with reduced abundance of KACs!
Inflammation appears to be operative in the earliest stages of lung adenocarcinoma development and likely drives oncogenesis of alveolar intermediate cells that function in tissue repair. Indeed, it has been suggested that tumors are wounds that do not heal, and it is in this chronic healing process that the budding tumor can hijack inherent properties in the lung. It is also plausible that targeting inflammation is valuable for intercepting lung cancer rather than treating the disease in advanced stages. This supposition is supportive of earlier clinical studies with the IL-1B antibody canakinumab.
Very proud of this joint work with Linghua Wang and led by Fuduan Peng joint fellow with the Wang group, now director extraordinaire Ansam Sinjab, and Yibo Dai, and Warapen. Very proud of my lab who showed exemplary teamwork. I am also grateful for collaborations with many groups Junya Fujimoto that I personally learned so much from. This work could not have been done without funding from National Cancer Institute (NCI)(NIH funding is important!), Cancer Prevention and Research Institute of Texas and LUNGevity Foundation.”
Title: Multimodal spatial-omics reveal co-evolution of alveolar progenitors and proinflammatory niches in progression of lung precursor lesions
Authors: Fuduan Peng, Ansam Sinjab, Yibo Dai, Warapen Treekitkarnmongkol, Sujuan Yang, Lorena I. Gomez Bolanos, Tieling Zhou, Minyue Chen, Alejandra G. Serrano, Avantika Krishna, Nastaran Karimi, Manvi Sharma, Akshay Basi, Guangsheng Pei, Jianlong Liao, Yunhe Liu, Jiping Feng, Zahraa Rahal, Yang Liu, Jiahui Jiang, Kai Yu, Tala Noun, Yuejiang Liu, Khaja Khan, Kyung Serk Cho, Jichao Chen, Luisa M. Solis, Sarah Mazzilli, Steven Dubinett, Tina Cascone, Avrum E. Spira, Stephen Swisher, Naoe Jimbo, Takuo Hayashi, Satsuki Kishikawa, Kazuya Takamochi, Tomoo Itoh, Takashi Yao, Kenji Suzuki, Neda Kalhor, Ignacio I. Wistuba, Mingyao Li, Seyed Javad Moghaddam, Junya Fujimoto, Jared Burks, Jeffrey Myers, Kadir Akdemir, Linghua Wang, Humam Kadara.
You can read the full article in Cancer Cell by Cell Press.
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