Lamins

Lamin A loss tracks prostate cancer's progression

Undergraduate researcherMcCord Genome Labwith Dr. Rebeca San MartinMay–Dec 2021Published — AACR, Cancer Res 2023Immunohistochemistry, tissue microarray scoring

Lamin A loss identified as a candidate early biomarker for progressionp < 0.0001 on every comparison against carcinoma3rd author, AACR 2023

Context

Prostate cancer is one of the leading causes of cancer death in men. Lamin A and Lamin C are structural, filamentous proteins that support the nuclear envelope, aiding chromatin organization, DNA replication and transcription. They're derived from the LMNA gene through alternative splicing.

Prior work in other cancers had linked altered lamin expression to malignancy, but not consistently in one direction — some cancers show a gain, others a loss, depending on tissue type and stage. Almost 1 in 8 men are diagnosed with prostate cancer every year. Understanding how Lamin A/C expression tracks disease progression could point toward alternative, earlier treatment targets.

Question

Does Lamin A/C content change consistently across the path from benign to metastatic tissue — and can that be quantified from patient histology rather than just cell lines?

Lamin expression in cancer doesn't move in one consistent direction across cancer types: some show a gain, others a loss. So the question is not whether it changes, but whether it changes the same way every time in this one disease.

Approach & rationale

I worked with Dr. Rebeca San Martin on her research into lamin protein expression in prostate cancer. In my project, I analyzed histological sections of patient tumors and found that as cancer worsens, Lamin A expression goes down while Lamin B1 stays relatively constant.

The fuller study, from the published methods, combined immunostaining, ChIP-seq, and Hi-C to characterize Lamin A, B1, and B2 across a panel of cell lines modeling progression in vitro — RWPE (normal epithelium), LNCaP (adenocarcinoma), VCaP and MDAPCa2a/b (bone metastatic) — then checked whether the same pattern held in patient tissue microarrays via immunohistochemistry, which is the piece I scored.

Methodology & iteration

Attempt — count Lamin A-positive nuclei straight off the image

TriedWorking from IHC-stained tissue microarray images, defining regions of interest and counting Lamin A-positive nuclei directly.

AssumedThat a straightforward count would hold up across diagnostic categories — that a nucleus either reads positive or it doesn't.

Fell shortSome ROIs were overcounted. That only became clear once the same tissue was independently scored for Lamin B2 and the two counts were compared side by side, since the two markers shouldn't diverge for reasons unrelated to biology.

Held upResolving discrepancies region by region. The corrected counts — 497 ROIs for Lamin A, 384 for Lamin B2 — carried into the final analysis, across prostatitis, hyperplasia, adenocarcinoma II and adenocarcinoma III tissue.

In short

Across the four diagnostic categories, the share of Lamin-A-positive nuclei dropped moving from chronic prostatitis and hyperplasia toward adenocarcinoma II and III, with every comparison against carcinoma significant at p < 0.0001.

Results

This matched the lab's parallel cell-line work: bone-metastatic lines showed the lowest Lamin A content of any line tested, while Lamin B1/B2 held steady across the whole progression series.

My part of this AACR abstract was the tissue microarray scoring above — the fuller abstract also covers ChIP-seq, Hi-C, and radial chromosome positioning run by my collaborators. The published figure brackets four of the six possible pairwise comparisons; prostatitis vs. hyperplasia and adeno II vs. adeno III are not among them.

Significance

San Martin R, Das P, Hossain S, McCord RP. "Nuclear lamin content as a biomarker for prostate cancer progression." Cancer Res 2023;83(11 Suppl):Abstract A061.

My counts were shown across a modeled continuum from normal epithelium to metastatic prostate cancer, leading to my name being third author.

Published AACR abstract page — The published abstract — AACR, Cancer Res 2023, Abstract A061.

Reflection

This was the first project I contributed to in the lab, under a postdoc, Dr. Rebeca San Martin, whose work focused on 3D genome organization — specifically lamins and LADs — across epithelial-to-metastatic progression in prostate cancer cell lines.

My job was to count nuclei in squamous epithelial cells; before I knew it, my entire summer was spent staring at and hand-counting nuclei. The images were beautiful — the staining made the tissue look like kaleidoscopic art — and there was something strange about finding that beautiful given what it represented.

It felt odd to be considered an author when all I'd done was count and could barely grasp the entirety of the project at the time. But working with Dr. San Martin reminded me of Dr. McCord — the way both of them held such depth of expertise that they could hand a piece of it to someone with almost no background and still trust the result. That was my first real model for what expertise looks like in practice.

The hierarchical nature of DNA folding inside a nucleus — lamins as the meshwork the B compartment attaches to — became even more interesting once I connected it to compartment switching itself, which bridged this project to what I later did with Heng Li on CTCF and cohesin as chromatin's structural proteins.

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